ECTRIMS: 'Wow' Results for Oral Fumarate in MS

by John Gever John Gever Senior Editor, MedPage Today
October 21, 2011

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain that dimethyl fumarate, an oral agent, significantly decreased the risk of relapse compared to placebo in patients with relapsing-remitting multiple sclerosis.

Note that flushing was a common side effect, and overall results did not differ whether dimethyl fumarate was dosed twice or three times a day.

AMSTERDAM -- Efficacy and safety data from a phase III trial of dimethyl fumarate (BG12) in relapsing-remitting multiple sclerosis were impressive enough to elicit a "wow" when they were shared with neurologists here.

Only about a quarter of patients who received the oral drug in either of two doses experienced a relapse during two years of treatment, compared with 46% of patients assigned to placebo (P<0.0001) in the randomized, double-blind study, said Ralf Gold, MD, of Ruhr University in Bochum, Germany.

Results for disability progression and burden of central nervous system lesions seen in MRI scans in the trial -- called DEFINE -- were also highly favorable for the drug.

Moreover, the only significant safety issues appeared to be flushing and gastrointestinal complaints, most of which were mild to moderate, Gold reported during a platform session at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

After Gold finished his presentation, one audience member went to the microphone and said, "I think I speak for many people when I say, wow."

Other neurologists were impressed as well, although more restrained in their reactions.

Per Soelberg-Sorensen, MD, of Copenhagen University Hospital in Denmark, said he found the efficacy data surprising.

"I would never have thought it would be in that range," he said, noting that results in an earlier phase II trial showed a narrower gap between the active-drug and placebo groups.

"Usually you don't see phase III results better than phase II results," said Soelberg-Sorensen, who was not involved in the study.

However, he also pointed out that the earlier trial's confidence intervals were broad enough that the findings may not actually conflict.

Dimethyl fumarate has a novel mechanism of action relative to existing MS drugs. It is believed to activate the nuclear factor-like 2 transcriptional pathway, thereby reducing oxidative stress that contributes strongly to demyelination.

The drug has also been used for many years in Europe and elsewhere to treat psoriasis.

The DEFINE study randomized 1,237 MS patients to receive placebo or 240 mg of dimethyl fumarate orally two or three times daily for 96 weeks. Patients were evaluated regularly for relapses, disability, and other MS manifestations, as well as for adverse events.

MRI scans were also performed periodically in a randomly selected subset of 540 patients.

Patients with primary or secondary progressive forms of MS were excluded from the study, as were those with recent relapses or use of corticosteroids.

The proportion of patients experiencing relapse during the two-year treatment period was the primary endpoint. Annualized relapse rates, MRI lesion burden, and disability progression were among the secondary outcome measures.

Because relapse was so central to the trial, an independent committee of eight neurologists had to confirm the examining physician's diagnosis using blinded records, with MRI scans withheld from consideration.

Gold reported results on an intent-to-treat basis. Although about 22% of participants (equal in the three study arms) failed to complete the two years of treatment, only about 3% were lost to follow-up, he said.

Withdrawals attributed to adverse events -- which could include relapse or other types of treatment inefficacy, as well as intolerable side effects -- were more common in the two fumarate groups than in the placebo group (about 10% versus 5%).

All of the differences between the active-drug groups and placebo were significant at P<0.05 and most at 0.001 or less.

There were only two deaths in the study, both from traffic accidents. Serious adverse events including malignancies and infections were evenly distributed between the study arms.

About one-third of patients in both fumarate groups reported flushing, compared with 5% of the placebo group.

Gold said this was a potential limitation of the study. Study protocols were designed to keep the efficacy evaluators from knowing about episodes of flushing and other potential drug side effects to preserve their blinding, he said.

But the patients themselves knew, and many of them may have deduced their treatment assignments, he conceded.

Soelberg-Sorensen worried that the flushing effect could be a problem for the drug in routine practice.

"The question is whether patients will tolerate the flushing, which could be worse postmarketing than in a clinical trial," he said.

On the other hand, Gold said, the flushing was seen mainly during the first month of treatment.

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